Safire was best known as a long-time syndicated political columnist for the New York Times and a regular contributor to "On Language" in the New York Times Magazine. He was the author of over fifteen books including novels, essays and books on language.

Safire was a speechwriter for President Richard Nixon and Vice-President Spiro Agnew in 1968. In 1978, he won a Pulitzer Prize in Journalism, and later served on the Pulitzer Board, beginning in 1995. His four novels are: Full Disclosure (1978), Freedom: A Novel of Abraham Lincoln and the Civil War (1987), Sleeper Spy (1995), and Scandalmonger (2000). He also edited anthologies, such as Lend Me Your Ears: Great Speeches in History (1997), books on language, such as On Language, The Right Word in the Right Place at the Right Time (2004), and books of political commentary, including Safire's Political Dictionary, first published in 1968, which went into three editions.